The present invention, in some embodiments thereof, relates to compositions and methods for treating malignant gliomas and, more particularly, but not exclusively, for treating Glioblastoma multiforme (GBM).
Malignant gliomas, the most common adult-onset neurological neoplasms, encompass a family of primary central nervous system tumors including glioblastoma, astrocytoma, oligodendroglioma, and ependymoma, along with the juvenile onset neoplasms such as juvenile pilocystic astrocytoma.
Malignant gliomas are typically characterized by over-expression of growth factors/tumor associated antigens believed to significantly contribute to the unchecked growth of such tumors. Various malignant gliomas, such as glioblastomas, exhibit epidermal growth factor receptor (EGFR) overexpression leading to increased aggressiveness and poor prognosis. Malignant gliomas may also display over-expression of platelet-derived growth factor receptor, a phenomenon which has also been correlated with increased malignancy and poor prognosis.
Malignant gliomas, the most common type of primary brain tumors, are aggressive, highly invasive, and neurologically destructive tumors which are among the deadliest of all human cancers. Of the estimated 17,000 new brain tumors diagnosed each year in the United States, about half are malignant gliomas. Malignant glioma cells produce very invasive brain tumors with infiltration of both white and gray matter. At the time of diagnosis, microscopic extension through much of the neural axis by malignant glioma is the rule. Such extension by motile invading cells underlies the incurability by surgery of most gliomas, even when they appear small and restricted in nature.
Glioblastoma multiforme (GBM), the most serious form of malignant glioma, are extremely aggressive brain tumors which generally arise in the upper brain (cerebrum), but which may also occur elsewhere in the central nervous system, such as in the spinal cord, cerebellum, brain stem, or optic chiasm. Low-grade gliomas, which include astrocytomas, oligodendrogliomas, and pilocytic astrocytomas, account for 25% of all primary brain tumors, and over time most of these low-grade tumors dedifferentiate into more malignant gliomas. Diffuse astrocytomas are predominantly located in the cerebral hemispheres of adults and have an inherent tendency to progress to anaplastic astrocytoma and (secondary) glioblastoma. The majority of glioblastomas develop de novo (primary glioblastomas), without an identifiable less-malignant precursor lesion.
Despite optimal therapy with surgery, radiotherapy, and temozolomide chemotherapy, the median survival of patients with glioblastomas is only 12-15 months. When these tumors recur, conventional salvage therapies produce minimal benefit, with only 8-15% of patients alive and free from progression at 6 months (6M-PFS).
Neovascularization is a major feature of glioblastomas (Maher et al., 2001, Genes Dev. 15:1311-1333). Angiogenesis activators are extremely important in tumor growth, as reflected by the fact that neovascularization must occur for solid tumors to grow beyond a diameter of 2-3 mm (Goldbrunner et al., 2000, J. Neurooncol. 50:53-62). One of the molecules that regulates this process is the vascular endothelial growth factor (VEGF). VEGF mRNA is overexpressed in the highly vascularized glioblastoma multiform (Maher et al., 2001, Genes Dev. 15:1311-1333). It has been demonstrated that the transfection of antisense-VEGF-complementary-DNA as well VEGF antisense RNA encoding vectors result in down-regulation of the endogenous VEGF and inhibits growth of gliomas in mice (Sasaki et al., 1999, Int. J. Dev. Neurosci. 17:579-591; Zheng et al., 2000, Acta Pharmacol. Sin. 21:211-214). A similar effect was observed upon the local delivery of the angiogenesis inhibitor endostatin (Read et al., 2001, Nat. Biotechnol. 19:29-34). However, this strategy has a cytostatic effect. It is effective in inhibiting tumor growth but not in actually eliminating them.
Bevacizumab (Avastin®) is a humanized monoclonal antibody that binds VEGF, preventing it from activating its receptors, especially VEGFR2, abrogating subsequent biologic effects. This drug has shown benefit in colorectal, non-small cell lung, and breast cancers, and is approved by the Food and Drug Administration for these indications. Several studies have now evaluated the combination of bevacizumab and the chemotherapeutic agent irinotecan in recurrent malignant gliomas and the results have been more encouraging.
In one phase II study, the combination of bevacizumab and irinotecan produced a response rate of 67% and 6M-PFS of 56% in recurrent anaplastic gliomas, and a response rate of 57% and a 6M-PFS of 46% in recurrent glioblastomas.
These preliminary findings have been recently confirmed by a large multi-center randomized phase II study of 167 patients with recurrent GBM who were treated with bevacizumab alone or in combination with irinotecan [Cloughesy T, Prados M, Wen P, et al. Society for Neuro-Oncology 12th Annual Meeting, 2007].
Patients receiving bevacizumab alone had a response rate of 20% and a 6M-PFS of 35.1%, while patients receiving the combination of bevacizumab in combination with irinotecan had a response rate of 34% and 6M-PFS of 51%. The median survival was 9.7 months for bevacizumab (Avastin) alone, and 8.7 months for the combination. In addition, treatment with bevacizumab was also associated with a significant reduction in peritumoral edema and the need for corticosteroids. As a result of these studies, the combination of bevacizumab with irinotecan is increasingly used for the treatment of patients with recurrent malignant gliomas.
Another agent proposed for the treatment of malignant gliomas is Aflibercept (VEGF-Trap). This is a soluble hybrid receptor, composed of portions of VEGFR-1 and VEGFR-2 fused to an immunoglobulin G1 Fc domain. Like bevacizumab, it is designed to deplete circulating VEGF, but has significantly greater affinity for VEGF than bevacizumab itself.
In addition, inhibitors of VEGF receptors have been proposed for the treatment of malignant gliomas. In a phase II trial study of a potent pan-VEGFR inhibitor, cediranib (AZD2171; Recentin) in patients with recurrent glioblastomas, response rates in excess of 50% were observed and the 6M-PFS was increased to approximately 25%. Studies with other inhibitors of VEGFR such as sorafenib (Nexavar), sunitinib (Sutent), vandetanib (ZD6474; Zactima), pazopanib (GW786034), and vatalanib (PTK787) in glioblastomas are also in progress.
In comparison with drugs targeting VEGF or VEGFR, agents inhibiting other angiogenic pathways have produced less success. Drugs that inhibit PDGF receptors such as imatinib mesylate (Gleevec) were ineffective, due partly to its poor penetration across the blood-brain barrier. Cilengitide, a drug that inhibits αvβ3 and αvβ5 integrins has shown modest activity in glioblastomas and studies combining it with other agents are in progress.
The use of viral vectors as gene delivery agents has been proposed for the treatment of malignant gliomas. Such viruses may be engineered to produce anticancer activity by expressing transgenes whose products exert a tumoricidal effect.
Several of such approaches have shown anti-tumor efficiency in experimental studies, and the first clinical trials for the treatment of malignant glioma were conducted in the 1990s. HSV-tk gene therapy has been the pioneering and most commonly used approach, but oncolytic conditionally replicating adenoviruses and herpes simplex virus mutant vectors, p53, interleukins, interferons, and antisense oligonucleotides have also been used.
U.S. Pat. No. 5,747,340 teaches use of a murine endothelial cell-specific promoter which shows selectivity towards angiogenic cells.
International Application WO/2008/132729 teaches viral vectors comprising endothelial cell specific promoters which directs expression of a transgene in angiogenic cells for the treatment of cancer.